New phenyloxy and phenylalkoxy benzoic acid amides



3,051,796 NEW PHENYLOXY AN 1) PMNYLALKOXY BENZOIC ACE ES Hans Suter and Hans Zutter, Schafihausen, Switzerland, assignors to Eprova Limited, Schafi'hansen, Switzerland No Drawing. Filed June 3, 1960, Ser. No. 33,643 Claims priority, application Switzerland June 11, 1959 7 Claims. (Cl. 260-2472) The present invention relates to a group of new compounds consisting of phenyloxy and phenylalkoxy benzoic acid aminoalkyl amides, which are suitable for and eifective in the treatment of disturbances of the heart rhythm (heart arrhythmia).

The new compounds of this invention may be represented by the following general formula:

wherein n is an integer selected from zero to four, preferably 1 to 4, Am is a member selected from the group consisting of lower alkyl lIIalkyleneN\ R1 lower alkyl N (H) NRa in which R, is selected from the group consisting of hydrogen and a lower alkyl radical, alkylene is a lower alkylene radical containing at least 2 carbon atoms,

A N R;

is a radical selected from the group consisting of piperidino, pyrrolidino and morpholino radicals and R is selected from the group consisting of a lower alkyl and a lower hydroxy alkyl radical.

The invention also includes the acid addition salts of the above free bases with pharmacologically acceptable inorganic and organic acids, such as for example hydrochloric acid, sulphuric acid, lactic acid, citric acid or oxalic acid.

The preferred compounds of the invention are the dialkylaminoethyl amides of the 4-phenyloxy and 4-phenylalkoxy benzoic acid.

The phenylalkoxy derivatives generally show a higher efiicacy than the phenyloxy derivatives, and they are consequently the compounds Which are of particular value.

It has been found that the compounds with the structure defined above are excellently suitable for the treatment of heart arrhythmia as so-called antiarrhythmics or anti-fibrillation agents. They are particularly characterised by an unusually high activity.

The anti-arrhythmic activities of the compounds according to the invention, as established in pharmacological test experiments and for example determined on the electrically stimulated isolated top of the right ventricle of the rat, showed activity values with rheobase, maximum frequency and excitation which are up to 100 times greater than those measured in concurrently conducted comparison experiments with procainamide (4-aminobenzoic acid-2-diethyl-aminoethyl amide).

This extraordinary difference can be attributed to a different type of action mechanism.

same Patented Aug. 28, 1962 its 4-aminobenzoic acid-2-diethylamino-ethylamide is the therapeutic compound hitherto most widely used for the present indication.

4-phenylethoxybenzoic acid-2' diethylaminoethylamide (see Example 3) is on average quite times more active than procainamide.

4-benzyloxy-benzoic acid 2 diethylaminoethylamide (Example 2) shows about half, and 4-phenoxy-benzoic acid-2-diethylaminoethylamide (Example 1) shows one third of the activity of the 4-phenylethoxy derivative (Example 3).

The acute toxicity of the compounds according to the invention is fairly low. It is only about twice as high as that of the very much less active 4-aminobenzoic acid- 2'-diethylaminoethylamide.

As a result, a therapeutic index is produced for the compounds according to the invention which is several times higher by comparison with the therapeutic compound most used at the present time.

The compounds according to the invention are suitable both for oral administration, for example in the form of the free bases or their crystallized salts, and also for introduction into the organism by injection in the form of aqueous solutions of the acid addition salts.

The compounds according to the invention are most easily prepared by conversion of a reactive derivative of a phenylox-y or phenylalkoxy benzoic acid, advantageously by conversion of a mixed acid anhydride thereof and an inorganic or organic acid, for example hydrochloric acid or a semi-ester carbonic acid, for example the ethyl carbonic acid, see Helv. chim. Acta 34 (1951), page 874, with a diamine of the formula wherein Am has the meaning defined above, and recovering the amide thus formed.

As mixed acid anhydride, it is advantageous to use the corresponding acid chloride.

The reaction itself is preferably carried out in a solvent which is neutral with respect to acid chlorides, advantageously in a halogenated hydrocarbon (for example chloroform). The diamine is used in at least the equivalent quantity, but preferably in excess, this particularly simplifying the working up.

The temperature at which the reaction is carried out can vary Within fairly wide limits, from less than 0 C. up to the boiling point of the solvent being used. The compounds according to the invention are generally isolated initially as a free base when using an excess of di amine, and as a hydrochloride addition salt when using exactly the equivalent quantity of diamine.

However salts with other acids which form addition salts with amines may be prepared by reaction of the free base, or the hydrohalide salts after conversion to the free base by treatment with a basic reagent such as sodium hydroxide or potassium carbonate, with the desired acid (e.g. sulphuric acid, nitric acid, lactic acid, tartaric acid, citric acid or oxalic acid, a pharmacologically acceptable acid being employed where the salt is to be the final compound). The above mentioned method is, however, not the only method which yields the desired compounds.

In addition to using any desired mixed acid anhydride as reactive derivative of a phenyloxy and phenylalkoxy benzoic acid, it is also possible to use an ester thereof, for example a methyl or cyanomethyl ester (see for example Helv. Chimica Acta 38 (1955) pages 69, 80, 83, 1508; 39 (1956) page 872). The actual reaction conditions must of course be adapted to the particular case. It is also in certain circumstances possible for the phenyloxy and phenylalkoxy benzoic acids to be directly reacted to form the amides.

Finally, the reaction with the amine of the general formula HAm can also be carried out in stages, by

(1) a reactive derivative of a phenyloxy and phenylalkoxy benzoic acid being first of all reacted with NH to an amide of the general formula and this thereafter being converted by reaction with a reactive ester of an aminoalcohol of the general formula HOalkyleneB into a compound of the Formula I, or by (2) a reactive derivative of a phenyloxy or phenyl alkoxy benzoic acid being first of all transformed by reaction with a reactive ester of an alcohol of the general formula H N-alkyleneOH reaction with a free aminoalcohol of the formula H N-alkyleneOH and subsequent esterification into a reactive ester of a hydroxy alkyl amide of the general formula and thereafter this reactive ester is converted by further reaction with an amine of the general formula into a compound of the general Formula I.

The invention is further illustrated by the following examples:

EXAMPLE 1 4-Phen0xy-Benz0ic Acid-2'-Diethylaminoethylamide 25.7 parts by weight of 4-phenoxy benzoic acid and 60 parts by volume of thionyl chloride are boiled under reflux for 6 hours. The excess thionyl chloride is distilled ofi in vacuo. The resultant residue is taken up in a little alcohol-free chloroform and again evaporated. This operation is repeated once more.

' In this way, there are obtained 28 parts by weight (i.e. about 100% of the theoretical) of 4-phenoxybenzoyl chloride.

acid chloride is dissolved in 60 parts by volume of chloroform and added dropwise over a period of 1 hour and while stirring to a solution of 29 parts by weight of Z-diethylaminoethylamine in 150 parts by volume of chloroform. The reaction solution is then concentrated by evaporation in vacuo.

The evaporation residue is taken up in diethylether and a large quantity of water and shaken. The ethereal solution is separated out and repeatedly washed with water. After evaporating the dried ether solution, there remain 35 parts by weight of a thickly liquid oil, consisting of 4-phenoxybenzoic acid'-2'-diethylaminoethylamide, which is scarcely soluble in water, but is readily soluble in dilute aqueous mineral acids and organic solvents.

Micro-analysis, calculated for C H O N (molecular weight 312.40)

C calculated 73.04%; found 73.09%. H calculated 7.74%; found 7.57%. N calculated 8.97%; found 8.73%.

The hydrochloride of this aminoalkylamide is obtained by dissolving the base in dry ether and adding one quivalent of ethereal hydrogen chloride. The hydrogen chloride initially precipitates in the form of an oil. The ether is decanted and the oily salt is triturated with ethy acetate, whereupon it crystallizes. After recrystallization from ethyl acetate with addition of some i-propanol or from benzene, the hydrochloride melts at 114 to 116 C. It is readily soluble in Water, alcohols and chloroform, but is less soluble in cold ethyl acetate, benzene and petroleum ether.

1 EXAMPLE 2 4-Benzyl0xy Benzoic Acid-Z'-Diethwlaminoethylamide parts by weight of 4benzyloxy benzoic acid and 100 parts by weight of thionyl chloride are gently boiled for about 4 hours under reflux. The excess thionyl chloride is evaporated. The evaporation residue is taken up in chloroform and the solution again concentrated by evaporation. The 4-benzyloxy benzoyl chloride thus obtained is dissolved in 70 parts by volume of chloroform, and added dropwise over a period of approximately 1 hour and while stirring to a solution of parts by weight of 2-diethylamin0ethylamine in 150 parts by volume of chloroform. The reaction solution is concentrated by evaporation, the residue is taken up in ether and water, the ether solution is separated, washed with water and evaporated. The evaporation residue crystallizes after a short time. It can be recrystallized from a large quantity of petroleum ether (RP. 60 to 90 C.) or from a small quantity of i-propylether or from a mixture of both.

The 4-benzyloxy benzoic acid-2'-diethylaminoethylamide obtained in this manner melts at 64 to 65 C. It is readily soluble in most organic solvents and in aqueous dilute mineral acids, but is scarcely soluble in water.

Microanalysis, calculated for C H O N (molecular weight 326.42)

C calculated 73.59%; found 73.89%. H calculated 8.03%; found 8.00%. N calculated 8.58%; found 8.57%.

1 EXAMPLE 3 4-Phenylethoxy Benzoic Acid-2'-Diethylamin0ethylamide 18.1 parts by weight of 4-phenylethoxybenzoic acid and parts by volume of thionyl chloride are boiled under reflux for 6 hours. The solution is then concentrated by evaporation and the residue is treated with chloroform as described in Example 1. The 4-phenylethoxybenzyl chloride thus obtained is dissolved in parts by volume of alcohol-free chloroform and added dropwise in about 1 hour to a solution of 18.6 parts by weight of 2'-diethyl aminoethylamine in 150 parts by volume of chloroform.

After another hour, the reaction solution is concentrated by evaporation and the residue is taken up in diethyl ether and a large quantity of Water and shaken. The ethereal solution is separated, repeatedly washed in water, dried and evaporated. The residue (23.4 parts by weight, i.e. 92% of the theoretical), consisting of 4-phenylethoxybenzoic acid-2-diethylaminoethylamide, crystallises on being triturated with petroleum ether. It can be recrystallized from petroleum ether (HP. 60 to 90 C.).

Melting point: to 66 C.

Microanalysis, calculated for C H O N (molecular weight 340.45)

C calculated 74.08%; found 74.29%. H calculated 8.29%; found 8.19% N calculated 8.23%; found 8.26%.

base into one of its pharmacologically acceptable watersoluble salts, in which case the procedure is for example as follows:

(a) 5.0 g. of the free base (molecular weight 340.45) are dissolved in 14.7 cc. of extremely pure normal hydrochloric acid solution (the exactly equivalent quantity), brought to the desired concentration by adding extremely pure twice distilled water, filtered until sterile after control of the pH value, placed in ampoules and if necessary sterilized again.

(12) 5.0 g. of the free base are mixed with 14.7 ccm. of a pure normal aqueous lactic acid solution and the solution which is obtained is further treated as in the above Example (:1).

EXAMPLE 4 4-Phenyleth0xy Benzoz'c Acid-3-Dimethylamino-n-Propyl- Amide Replacement of 2-diethylaminoethylamine in Example 3 by 163 parts by weight of 3'-dimethylamino-n-propylamine provides in exactly the same way 4-phenylethoxybenzoic acid-3-dimethylaminon-propylamide, which is recrystallized from petroleum ether. (RP. 60 to 90 C.)

Melting point 70 to 72 C.

Microanalysis, calculated for C H O N (molecular weight 326.43)

C calculated 73.59%; found 73.30%. H calculated 8.03 found 7.84% N calculated 8.58%; found 8.37%.

4-phenylethoxy-benzoic acid 3' dimethylamino propylamide is scarcely soluble in water but is more readily soluble in dilute mineral acids, dilute aqueous lactic acid, citric acid, tartaric acid and oxalic acid and is very readily soluble in most organic solvents with the exception of cold petroleum ether, diisopropyl ether and cold benzine.

EXAMPLE 5 4-Phenyleth0xybenzoic Acid-2'-N(pz'perz'dino)Ethylamide The replacement of Z-diethylaminoethylamine of Example 3 by 205 parts by Weight of N(2-aminoethyl)- piperidine provides in analogous manner the 4-phenylethoxy-benzoic acid-2'-N(piperidino)ethylamide, which immediately crystallizes in the impure form. It can be successfully recrystallized from a relatively large volume of petroleum ether (B.P. 60 to 90 C.) or from i-propanol diluted with a little water.

Melting point 111 to 112 C.

Microanalysis calculated for C H O N (molecular weight 352.46)

C calculated 74.96%; found 75.08% H calculated 8.01%; found 7.97% N calculated 7.95%; found 7.86%.

4-phenylethoxy-benzoic acid 2' N(piperidino) ethylamide is scarcely soluble in water and cold petroleum ether, more readily soluble in aqueous mineral acids, aqueous lactic acid, citric acid, tartaric acid and oxalic acid and very readily soluble in ethanol, acetone and ethyl acetate.

EXAMPLE 6 4-Phenyleth0xy-Benzoic Acid-2 -N (M orpholino) Ethyl- N -M ethylamide 6.4 parts by weight of 4-phenylethoxy benzoic acid chloride are dissolved in about 20 parts by volume of chloroform and added dropwise in about 1 hour to a solution of 7.4 parts by weight of N(N-methylaminoethyl)morpholine in 35 parts by volume of chloroform. The reaction solution is then concentrated by evaporation. The residue is taken up in ether and water. The ethereal solution is separated out, washed with water and evaporated. The residue (8.1 parts by weight, i.e. 88% of the theoretical) crystallizes on standing and can be recrystallized from di-i-propylether or a few ethyl acetate. The obtained 4-phenylethoxy-benzoic acid-2 N (morpholino)- 6 ethyl-N'-methylamide melts at 107 to 108 C. It is readily soluble in lower alcohols, chloroform, ethyl acetate and dilute mineral acids, but scarcely soluble in water and benzines.

Equivalent weight: calculated for C H O N calculated: 368.46; found 370.

The hydrochloride of this compound melts after recrystallization from i-propanol at 184 to C. It is readily soluble in water, chloroform and in lower alcohols, but is less soluble in benzine.

Microanalysis calculated for C H O N Cl (molecular weight 404.93)

Cl calculated 8.76%; found 8.76%

EXAMPLE 7 4-Phenylethoxy-Benzoic Acid-ZN-(Pyrrolidino) Ethylamide Replacement of N(N'-methy1aminoethyl)morpholine in Example 6 by about 6 parts by weight of N(2-aminoethyl)-pyrrolidine provides in analogous manner the 4- phenyl-ethoxy-benzoic acid-2-N (pyrrolidino) ethyl amide. It is scarcely soluble in Water but readily soluble in dilute mineral acids and lower alcohols.

EXAMPLE 8 N (4-Phenylethoxy-Benzoyl N '-M ethylpiperazine 5 parts by weight of 4-phenylethoxy-benzoyl chloride are dissolved in about 10 parts by volume of chloroform and added dropwise while stirring to a solution of 4.5 parts by weight of N-methyl-piperazine in 20 parts by volume of CHCl The reaction solution is evaporated to dryness. The residue is taken up in water and diethyl ether and shaken. The etheral solution is separated out, washed with water, dryed and evaporated. The resultant residue N(4 phenylethoxy-benzoyl)-N-methyl-piperazine (7.3 parts by weight) is a viscous oil, which is scarcely soluble in Water but readily soluble in aqueous dilute mineral acids and in most organic solvents.

The hydrochloride melts after recrystallization from a mixture of ethyl acetate and i-propanol at 204 C.

Microanalysis, calculated for C H O N Cl (molecular Weight 360.88)

C calculated 66.56%; found 66.79%. H calculated 6.94%; found 7.08%. N calculated 7.77%; found 7.82%. Cl calculated 9.83%; found 9.60%.

The hydrochloride is readily soluble in water, chloroform, methanol, ethanol and hot i-propanol, but sparingly soluble in cold ethyl acetate and benzine.

EXAMPLE 9 N (4 Phenylethoxy-Benzoyl -N 2-H ydroxyethyl Piperazine 5 parts by weight of 4-phenylethoxy-benzoyl chloride in 10 parts by volume of chloroform are added dropwise while stirring to 6 parts by weight of N-(2-hydroxyethyl)- piperazine in 20 parts by volume of chloroform. The reaction mixture is diluted With chloroform and repeatedly washed with water, dryed and evaporated. The viscous oily residue (6.3 parts by weight) free N(4- phenylethoxy-benzoyl N 2' (hydroxyethyl-piperazine is sparingly soluble in water and diethyl ether. It is dissolved in ethyl acetate and converted by addition of etheric hydrochloric acid to the hydrochloride, which melts after twice recrystallization from i-propanol at 183 C.

Microanalysis, calculated for C21H2703N2C1 (molecular weight 390.94)

N calculated 7.16%; found 7.00%. Cl calculated 9.06%; found 9.13%.

The hydrochloride is readily soluble in water, acetic 7 acid, hot ethanol. and i-propanol andsoluble in chloroisthe radical selected from the group consisting of piperiform, but scarcely soluble in other solvents. dino, pyrrolidino and morpholino radicals, and R is se- As stated above, the herewith described, new aminolectedfrom-the group consisting of the lower alkyl and alkylamine compounds have proved to be effective agents, lower hydroxyalkyl .radical, and acid addition salts of which are useful in the treatment of disturbances of the 5 said amino alkyl amide with pharmacologically acceptable heart rhythms. They are very well tolerated and do not inorganic and organic acids. show undesired secondary effects. In pharmacological ex- 2. The 4-benzyloxy-benzoic acid-2-diethylaminoethylperiments in vitro and the dog, an excellent antiarrhythmic mide f the formula activity of the new compounds was disclosed against eX- perimental induced pathogenic arrhythmias. I For oral 0 7 application the compounds can be given in capsules of CHPO CONH OHFGEPN 0.5 g. and for intravenous use they can be applied as salt 0 H; solutions in ampoules. The preferred daily dose is be- 3 The tween 0.3 g. and 3.0 g. (in most cases 0.5 to 2 g.).

The antiarrhythmic activity in men and the therapeutic effect with regard to its safe, eflective and reliable use- 0135 fulness were verified in clinical tests, for instance with @OHTOHrWQCONECHFCHTN/ 4-phenyl-ethoxybenzoic acid 2 diethylaminoethylamide (see Example 3). In most cases a prompt and continual disappearance of the pathological arrhythmic phenomena 4. The 4-phenylethoxy-benzoic acid-3'-diethylamino- 4-phenylethoxybenzoic acid-2'-diethylaminoethyl-amide of the formula could be obtained. propyl-arnide of the formula @Ofl -OlIz-O-CONHCH2CHzCHz-N GHQ What we claim is: V i 5. The 4-phenylethoxy benzoic acid-2'-N(piperidino)- 1. A chemical compound selected from the group conethylamide of the formula orn-oHP0 @-o0NH-omom-N\ 11 sisting of 4-phenyloxy and 4-phenylalkoxy benzoic acid 6. The 4-phenylethoxy benzoic acid2-N-(m0rphoamino alkyl amide of the formula lino)-ethyl-N-methyl-amide of the formula CH n-O- 00-11 Q m OHTOHTOQCOMMM (H) 0 a wherein n is an integer selected from zero to four, Am is a member selected from the group consisting of lower alkyl 7. The N(4-pheny1ethoxybenzoyl) N methyl-pipera- 40 zine oVf the formula V Nalkylene-N R:

R1 References Cited in the file of this patent and UNITED STATES PATENTS -N (H) N-R 2,504,617 Anish Apr. 18, 1950 2,629,737 Krimmel Feb. 24, 1953 in which R is selected from the group consisting of hy- 2,688,026 Krimmel Aug. 31, 1954 drogen and the lower alkyl radical, alkylene is the lower 2,865,911 Nielsen et a1. Dec. 23, 1958 alkylene radical of at least 2 carbon atoms, 2,870,145 Perron Ian. 20, 1959 N R 2,948,736 Martin Aug. 9, 1960 1 

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4-PHENYLOXY AND 4-PHENYLLALKOXY BENZOIC ACID AMINO ALKYL AMIDE OF THE FORMULA
 6. THE 4-PHENYLETHOXY BENZOIC ACID-2''-N-(MORPHOLINO)-ETHYL-N-METHYL-AMIDE OF THE FORMULA 